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Title Intervention of non-small cell line cancer oncogenic pathways with delta-tocotrienol
Publication Date
Degree PhD
Discipline/Department Nutrition and Food Science
Degree Level doctoral
University/Publisher Wayne State University
Abstract Non-small cell lung cancer (NSCLC) is most hostile and leading cause of cancer deaths in the United States. Clinical data has demonstrated that 30 % of NSCLC patients have increased Notch activity and 10% of NSCLC have gain-of-function mutation on Notch-1 gene. Our data demonstrated that delta-tocotrienol could inhibit NSCLC cells proliferation, invasion and induce apoptosis by down-regulation of the Notch-1 signaling pathway. Using microRNA microarray and microRNA transfection, our findings further suggest that delta-tocotrienol is a non-toxic activator of miR-34a which can inhibit NSCLC cell proliferation, induce apoptosis, and inhibit invasion. Last but not the least, We observed that delta-tocotrienol individually or in combination with cisplatin exhibited potent anticancer abilities in NSCLC cells by down-regulating oncogenic pathways such as Notch-1 and NF-ĸB pathways and up-regulating the tumor suppressor pathways such as Bcl-2, caspase-3. Decreased NF- κB activity was observed in both cell lines in combination treatment along with significantly reduced levels of angiogenic factors MMP-9, VEGF thus offering a potential starting point for the design of novel anticancer agents. Overall, our results suggest that delta-tocotrienol could be a promising approach for designing tailored novel combination therapies for the treatment of human NSCLC.
Subjects/Keywords delta-tocotrienol, lung cancer, Notch-1; Nutrition
Contributors Smiti Gupta
Rights Open Access Dissertation
Country of Publication us
Record ID oai:digitalcommons.wayne.edu:oa_dissertations-1545
Repository wayne
Date Retrieved
Date Indexed 2020-07-20
Created Date 2012-01-01 08:00:00

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…HMG-CoA) reductase (63). Studies indicate that delta and gamma- 10 tocotrienol enhance HMG-CoA reductase ubiquitination and degradation. In addition, deltatocotrienol could block the processing of sterol regulatory element-binding…

…tocotrienols demonstrated improved T- cell function in old mice (70). 11 Fig.1.2 Chemical Structure of Tocotrienols (71) Although α-tocotrienol seems to offer the most neuroprotection, among all the vitamin E isomers, γ and δ-tocotrienols…

…targeting Notch signaling in NSCLC with minimal toxicity might provide new impetus in this area. We hypothesize that deltatocotrienol will reduce NSCLC cell growth via inhibition of Notch-1 signaling pathway which in turn can be used as a sensitizer to…

…cisplatin. Specific Aim 1: To determine the anti-cancer activity of delta -tocotrienol against different NSCLC cells and elucidate its in vitro effect on Notch-1 and NF-ĸB signaling pathways. We characterized anti-cancer effects of delta -tocotrienol on…

…NSCLC cell lines overexpression Notch-1. Since there is lack of data showing the effect of delta-tocotrienol on NSCLC cell lines overexpressing Notch-1, we identified molecular mechanisms on these cell lines. Specifically, we investigated the Notch-1…

…cellular pathway and also the transcription factor NF-ĸB pathway. First, we determined the deltatocotrienol IC50 (half inhibition concentration) on these three cell lines by MTS 14 assay. Second, we tested delta –tocotrienol’s ability for the…

…inhibition of cell growth of these cell lines by flow cytometry. Third, we detected gene expression regulation effect of deltatocotrienol on the nuclear transcription factor. NF-ĸB activity was measured by electrophoretic mobility shift assay (EMSA…

…x28;miRNA) microarray, we found the inhibition of NSCLC cell growth and induction of apoptosis by delta-tocotrienol due to modulation of Notch-1 pathway mediated through alteration of specific miRNA expression. Pre-miRNA transfection was utilized…